Basic ethers of hydroxy anthraquinones



S s P t -m BASIC ETHERS F HY DROXY ANTHRAQUINONES Wilhelm Wenner, UpperMontclair, N.J., assignor to Hotfmann-La Roche Inc., Nutley, NJ., acorporation of New Jersey No Drawing. Application February 14, 1957Serial No. 640,088

17 Claims. (Cl. 260-294.

This invention relates to basic ethers of hydr'oxy anthraquinones. Moreparticularly, the invention relates to monoand his tertiary amino alkylderivativesof mono and dihydroxy anthraquinones, respectively. The novelbases may be represented by the following structural formula wherein Rrepresents a tertiary amino alkoxy group and R represents hydrogen or atertiary amino alkoxy group, at least one R representing hydrogen.

Either one or both substituents represented by R may represent hydrogenso that anthraquinone derivatives containing only one or two basic ethergroups are contemplated. Also included within the scope of the inventionare acid addition salts and quaternary ammonium salts of the basesrepresented by the above formula.

The tertiary amino alkoxy groups represented by R; and R in the aboveformula include dialkylamino alkoxy groups and nitrogen heterocyclicalkoxy groups wherein the nitrogen atom of the heterocyclic ring isattached to a carbon atom of the alkoxy group. The. alkyl groups in thedialkylamino alkoxy substituent are preferably straight chain andbranched chain lower alkyl groups. The alkoxy portion of the basic ethersubstituent includes straight chain, and branched chain alkylene groups,preferably lower alkylene, joining the oxygen and nitrogen ice thefollowing structural formulae constitute the most preferred groups ofthis invention:

T lower alkyl 5 (I) (J-lower alkyleneower alkyl (III) I lower alkyl 0O-lower alkylene-N t ower alkyl lower alkyl -lower all: leney ower alkyl(IV) (I) O-lower alkylene-N H lower alkyl lower alkyl N-lower alkylene-0(I) O-lower alkylene-N lower alkyl lower alkyl 40 (VI) lower alkylO-lower alkylene- 0 lower alkyl N lower alkyl O-lower alkylene N loweralkyl 1 atoms.

Illustrative of the dialkylamino alkoxy substituents are dimethylaminomethoxy, diethylamino ethoxy, dimethylamino propoxy, dimethylaminoisopropoxy, diethylamino propoxy, dimethylamino butoxy, diethylaminobutoxy, diethylamino isobutoxy, dipropylamino butoxy, etc. Theheterocyclic radicals of the basic ether substituents are preferably 5or 6-membered saturated nitrogen monoheterocyclics, making up basicether groups-such as m0r-- pholinyl alkoxy, piperidyl alkoxy, pyrrolidylalkoxy, etc. The basic ether groups represented by R and R may be thesame or different.

Preferred bases of the invention may be described as including compoundsof Formula I above wherein R represents a radical selected from thegroup consisting of di-lower alkylamino alkoxy, piperidyl alkoxy,morpholinyl alkoxy and pyrrolidyl alkoxy and R represents a radicalselected from the group consisting of hydrogen, di-lower alkylaminoalkoxy, piperidyl alkoxy, morpholinyl alkoxy and pyrrolidyl alkoxy, atleast one R representing hydrogen, i.e. there is at least one but notmore than two basic ether groups in the molecule. Within that preferredclass of compounds those answering to the Formula I above wherein R is.in the 1-position are especially preferred. In particular, compoundshaving a basic ether group in the 1-position and corresponding to Thecompounds of this invention are produced by converting a monoordihydroxy anthraquinone into a salt thereof, preferably an alkali metalsalt, and reacting the salt produced with a tertiary amino alkyl halide.The reaction of the salt of the hydroxy anthraquinone and the tertiaryamino alkyl halide is preferably effected in an organic hydrocarbonsolvent such as benzene, toluene or xylene. The salt of the monoor.-dihydroxy anthra'-" quinone may be isolated prior to reaction with theamino alkyl halide or it may be formed'directly in the reaction mixturefrom the hydroxy anthraquinone and an alkali 6 hydroxide. The latterprocedure is preferred, Lg. the

salt of the hydroxy anthraquinone is produced by-sus-,

pending the dihydroxy anthraquinone in an organic hydrocarbon solventand adding a concentrated aqueous solution of a base such as ammoniumhydroxide or alkali. metal hydroxide such as sodium or potassiumhydroxide. Water is removed from the reaction mixture by refluxing andwhen the water is separated, the tertiary amino alkyl halide dissolvedin toluene or xylene isadded to there; action mixture. 2 When adihydroxy anthraquinone is utilized as'starting material, the additionof about one molar proportion of base and then about one molarproportion of tertiary amino alkyl halide will result in the productionprimarily of an anthraquinone derivative containing one metal group andone basic ether group, respectively. The second hydroxyl group remainssubstantially unchanged. If, however, about two molar proportions ofbase and tertiary amino alkyl halide are used per molar proportion ofdihydroxy anthraquinone, both hydroxyl groups undergo reaction and ananthraquinone derivative containing two basic ether groups is primarilyproduced.

The mono hydroxy-mono tertiary amino alkoxy anthraquinone produced asdescribed above may be isolated and, if desired, may be subsequentlyreacted with a second molar proportion of base and of tertiary aminoalkyl halide to produce an anthraquinone derivative contain: ing twobasic ether groups. The intermediate compounds which havethe structuralformula (v11) 0 II R: I

wherein R represents a tertiary amino alkoxy group, one R representshydrogen and the other R represents hydroxy are also within the scope ofthis invention, R represents the same tertiary amino alkoxy groupsrepresented by R and R; as described in relation to Formula I above.

The compounds described above form acid addition salts by reaction witha variety of inorganic and organic acids and form quaternary ammoniumsalts by reaction with quaternizing agents. Illustrative acid additionsalts include hydrohalides such as the hydrochloride, hydrobromide,hydroiodide, etc., sulfate, phosphate, nitrate, toluene sulfonate,citrate, oxalate, ascorbate, etc. Quaternary ammonium salts may beformed with alkyl halides, preferably lower alkyl halides such as methylchloride, methyl bromide, methyl iodide, ethyl iodide, propyl chloride,propyl bromide, butyl chloride and butyl bromide, alkenyl halides suchas allyl bromide, crotyl bromide, etc., aralkyl halides such as benzylchloride, benzyl bromide, methoxybenzyl chloride, phenethyl chloride,etc. and alkyl sulfates such as dimethyl sulfate, diethyl sulfate, etc.Phar'maceutically acceptable salts such as those illustrated above andsalts containing one or' more acid or quaternary groups in the moleculeare contemplated.

The compounds of this invention have-.utility as anthelmintics andantiprotozoan agents being useful in combatting infections caused byorganisms such as Syphaeia obvelata and Trichomonqs vagiizalis. Thecompounds. may be administered orally or parenterally or, in some cases,topically by combining therapeutic doses with conventional carriersand/or excipients to prepare tablets, injectables or ointments, as thecase may be, according to accepted pharmaceutical practice.

The following examples are illustrative of the invention. Alltemperatures arev expressed in degrees centigrade.

' Example 1 67 g. of l-hydroxyanthraquinone were stirred with withwater, and then extracted with dilute hydrochloric acid. The acidextract was made alkaline with ammonia. An oil separated whichcrystallized on standing. It was filtered and dried. The crudel-(2-diethylaminoethoxy)- anthraquinone base melted at 45-50. Thehydrochloride was prepared by dissolving the base in about 4 volumes ofalcohol and adding alcoholic hydrochloric acid in excess. Thehydrochloride crystallized slowly. It was filtered after standingovernight. The compound was recrystallized from about 20 volumes ofalcohol. It melted at 227-228".

5 g. of l-(2-diethylaminoethoxy)anthraquinone were dissolved in 50 cc.alcohol. After addition of 3 cc. of methyl iodide, the mixture wasallowed to stand at room temperature.- The methiodide crystallizedslowly. It was filtered after 3 days and was recrystallized from about300 cc. alcohol. The pure methiodide of1-(2-diethylaminoethoxy)anthraquinone melted at 197499".

8 g. of l- (2- diethylaminoethoxy)anthraquinone. were dissolved in 5 0cc. of methanol and mixed with 20 cc. of an 18% solution of methylbromide in methanol. After standing at room temperature for one day,ether was slowly added. The methobromide ofl-(2-diethylaminoethoxy)anthraquinone crystallized and was purified byre crystallization from isopropanol, M.P. 2l2-2l3.

Example 2 A solution of 17 g. of 2-(l-piperidyl)ethylchloridehydrochloride in 40 cc. of water was made alkaline with aqueous ammonia.The liberated base was extracted 3 times with 60 cc. portions oftoluene. The toluene extract was dried over potassium carbonate. Thefiltered solution was added to a suspension of 17 g. of the sodium saltof l-hydroxyanthraquinone in cc. of toluene. The mixture was refluxedwith stirring. After 8 hours, the solution was allowed to cool and wasfiltered. The filtrate was extracted with dilute hydrochloric acid. Thehydrochloride of the amino ether crystallized soon. It was filtered andrecrystallized from 150 cc. of water. The pure 1-[2-(1-piperidyl)ethoxy]anthraquinone hydrochloride melted at 248.

5 g. of 1-[2-(l-piperidyl)ethoxylanthraquinone hydrochloride weredissolved in water. The free base was liberated with ammonia andextracted with benzene. The benzene solution was evaporated and the freebase was obtained as the residue.

The free base obtained above was dissolved in alcohol. After addition of3 cc. of methyl iodide, the solution was allowed to stand for 2 days.The methiodide of l- 2-( l-piperidyl ethoxy] -anthraquinone was thenfiltered and recrystallized from methanol, M.P. 221222.

Example 3 15 g. of 2-(4-morpholinyl)ethyl chloride hydrochlorideweredissolved in 20 cc. of water. The solution was cooled and saturated withpotassium carbonate. The free base thus obtained was extractedrepeatedly with toluene. The toluene solution (ca 200 cc.) was driedover potassium carbonate and filtered. The filtrate was added to asuspension of'9 g. of dry sodium salt of lhydroxyanthraquinone in 100cc. of toluene. The mixture was refluxed for 12 hours. After cooling, itwas filtered. From the filtrate'the base was extracted with dilutehydrochloric acid. The acid extract was made alkaline with ammonia. Thel-[2-(4-morpholinyl)ethoxylanthraquinone crystallized immediately. Itwas filtered and recrystallized from alcohol and melted at -117.

4 g. of the base obtained above were dissolved in 100 cc. of hotalcohol. Alcoholic hydrochloric acid in excess was added. From the darksolution, the hydrochloride separated. on cooling, M.P. 213-214".

Example 4 16 g. of ,Z-dimethylarhinoisopropyl chloride hydrochloe ridewere dissolved in 30 cc.- of water. The base was precipitated byaddition of an excess of potassium carbonate and was extracted with 200cc. of toluene. The solution was dried over potassium carbonate and wasfiltered. The filtrate was added to a suspension of 19 g. of the sodiumsalt of l-hydroxyanthraquinone in 100 cc. of toluene. The mixture wasrefluxed for 15 hours. After cooling, the solution was filtered. Thefiltrate was extracted with dilute hydrochloride acid. The acid extractwas made alkaline with ammonia. The1-(2-dimethylaminoisopropoxy)anthraquinone precipitated as an oil whichsoon crystallized. It was recrystallized from 50% alcohol and melted at41.

6 g. of the base obtained above were dissolved in 50 .cc. of alcohol.The solution was neutralized with alcoholic hydrochloric acid. The clearsolution was diluted with ether. The1-(Z-dimethylaminoisopropoxy)anthraquinone hydrochloride crystallized,M.P. 196-497.

Example 5 -23 g. of l-hydroxyanthraquinone were stirred wtih 300 cc. ofxylene. A solution of 7 g. of potassium hydroxide in 25 cc. of water wasadded. The mixture was refluxed until no more water separated in thetrap inserted below the condenser. A solution of 3-dimethylaminopropylchloride, prepared from a concentrated aqueous solution of 18 g. of thehydrochloride with an excess of potassium carbonate and extraction withxylene, was added. The mixture was refluxed for 7 hours. After coolingit was filtered and extracted with dilute hydrochloric acid. The acidextract was made alkaline with ammonia. none separated in crystallineform. It was recrystallized from 50% alcohol and melted at 45.

8 g. of the base obtained above were dissolved in 100 cc. of acetone.Upon addition of alcoholic hydrochloric acid, the hydrochlorideseparated immediately. The hydrochloride was recrystallized fromisopropanol and melted at 197-198".

3 g. of the base obtained above were dissolved in 20 cc. of methanol and3 cc. of methyl iodide were added. After a few minutes the methiodidestarted to crystallize. It was filtered the following day.Recrystallization from ca 30 cc. of methanol yielded 3 g. of the puremethiodide of 1-(3-dimethylamin0propoxy)anthraquinone, M.P. 236237.

Example 6 20 g. of 3-diethylaminopropyl chloride hydrochloride werestirred up with 30 cc. of water. Excess ammonia was added and the basewas extracted with toluene. The dried and filtered solution was added toa suspension of 25 g. of sodium salt of l-hydroxyanthraquinone intoluene. The mixture was refluxed for 8 hours. After cooling, it wasfiltered, the filtrate was extracted with 3 N hydrochloric acid and theextract was diluted with acetone. The1-(3-diethylaminopropoxy)anthraquinone hydrochloride crystallized onstanding, M.P. 2l0211.

Example 7 24 g. of l,2-dihydroxyanthraquinone were suspended in 300 cc.of xylene. At room temperature, a solution of 17 g. of potassiumhydroxide in 35 cc. of water was slowly added with stirring. Aftercomplete addition, the mixture was refluxed until all the water wasremoved. The mixture was then allowed to cool to about 50-60, and 28 g.of 2-diethylaminoethyl chloride were added. The mixture was thenrefluxed with stirring for 6 hours. After cooling, the solution wasfiltered. The filtrate was extracted repeatedly with dilute hydrochloricacid., The acid extract was made alkaline with ammonia and the1,2-bis(Z-diethylaminoethoxy)anthraquinone base was extracted withether. Part of the material crystallized from ether and was filtered off(see Example 8 below). The ether solution was dried over potassiumhydroxide The 1-(3-dimethylaminopropoxy)anthraqui- 6 andfiltered.Alcoholic hydrochloric acid was added. .01: standing in the refrigeratorthe hydrochloride crystallized. It was filtered and recrystallized from500 cc. of alcohol, yielding pure1,2-bis(2-diethylaminoethoxy)anthraquinone dihydrochloride, M.P. 227".

6.5 g. of the dihydrochloride obtained above were disolved in 50 cc. ofwater. The base was liberated with ammonia and was extracted with ether.The dried ether solution was evaporated and the free base1,2-bis(2-diethylaminoethoxy)anthraquinone was obtained in residue.

The base was dissolved in acetone. Methyl iodide (6 cc.) was added.After standing overnight, the bis(methiodide) of1,Z-bis(Z-diethylaminoethoxy)anthraquinone was filtered and dried. Itmelted at 230-231 and contained one mol of water of crystallization.

Example 8 The material which crystallized from the ethersolution of thebase in Example 7 was recrystallized from alcohol. The 1hydroxy-2-(Z-diethylaminoethoxy)anthraquinone thus obtained meltedat'106-l08.

The hydrochloride, prepared in water, crystallized from aqueous solutionand melted at 225229. The hydrobromide, prepared from an alcoholicsolution of the base with alcoholic hydrobromic acid, melted at 225-226.

5 g. of the base obtained above were dissolved in 100 cc. of methanol. 5cc. of methyl iodide were added. 01: standing, the methiodide of1-hydroxy-2-(Z-diethylaminoethoxy)anthraquinone crystallized. It wasrecrystallized from water and melted at 228-229.

Example 9 24 g. of 1,4-dihydroxyanthraquinone were stirred with 300 cc.of xylene. A solution of 15 g. of potassium hydroxide in 45 cc. of waterwas slowly added at room temperature. After complete addition, themixture was refluxed with continuous stirring. When the water had beenremoved, the mixture was allowed to coolto about 28 g. ofZ-diethylaminoethyl chloride were added and the mixture was refluxed for7 hours. After cooling, the solids were filtered off and the filtratewas distilled to dryness in vacuo. The residue was extracted with dilutehydrochloric acid. From the acid extract, the base was liberated withammonia and extracted with ether. The ether solution was distilled todryness and the residue was stirred up with petroleum ether. Onstanding, crystals separated. They were filtered and washed withpetroleum ether. The 1,4-bis(Z-diethylaminoethoxy)anthraquinone melts at60-61.

5 g. of the base obtained above were dissolved in 40 cc. of alcohol andneutralized with alcoholic hydrochloric acid. The clear solution wasdiluted with an equal volume of ether. On standing, the hydrochloridecrystallized. It was dissolved in 40 cc. of water, filtered, and dilutedwith 4 volumes of acetone. The pure1,4-bis(2-diethylaminoethoxy)anthraquinone dihydrochloride melted at235.

5 g. of the base obtained above were dissolved in 150 cc. of acetone.After addition of 5 cc. of methyl iodide, the mixture was allowed tostand for 3 days. The methiodide was filtered and recrystallized from amixture of 30 cc. of alcool and 60 cc. of methanol. The bis(methiodide)of 1,4-bis(diethylaminoethoxy)anthraquinone melted at 246.5-247.5

Example 10 24 g. of 1,4-dihydroxyanthraquinone were stirred with 300 cc.of xylene. A solution of 12 g. of potassium hydroxide in 40 cc. of waterwas slowly added. The mixture was then refluxed and the water wasseparated from the condensate by a trap. When the water had beenremoved, the free base, obtained from 37 g. of 2-dimethylaminoisopropylchloride hydrochloride with potassium carbonate and extraction with cc.xylene, was added and'the mixture was refluxed for 6 hours. Aftercooling, the solution was filtered and the filtrate was distilled todryness in vacuo. The residue was dissolved in chloroform and extractedwith diluterhydrochloric acidr From tli'ez'acirlextract1,4-bis(Z-dimethylaminoisopropoxy)anthraquinone base was liberatedwithammonia and extracted with ether. Addition of alcoholic hydrochloricacid precipitated the crude hydrochloride of the base obtained above.Recrystallization from isopropanol acetone (1:2) 1 gave the purehydrochloride of M.P. 217-219". It contains one mol of water ofcrystallization.

g. of the dihydrochloride obtained above were converted into the basewith ammonia. The 1,4-bis(2-dimethylaminoisopropoxy)anthraquinone wasextracted with ether and distilled to dryness.

The free base obtained above was dissolved in 50 cc. of acetone and anexcess of methyl iodide was added. On standing, the methiodidecrystallized. Recrystallization from 120 cc. of methanol gave the purebis(methiodide) of 1,4 bis(2 dimethylaminoisopropoxy)anthraquinone, M.P.2'63-264. It c'ontainsone mol'of water'of crystallization.

Ex'ample I1 24 g. of 1,4-dihydroxyanthraquinone were stirred with 300cc. of xylene. A solution of 12 g. of potassium hydroxide in 40 cc. ofwater was slowly added. The solution was refluxed with a trap until thewater was recovered. After cooling to about 60, a solution of3-dimethylaminopropyl chloride in xylene (prepared from itshydrochloride with potassium carbonate and extraction with 100 cc. ofxylene) was added and the mixture was refluxed for 6 hours. The solutionwas filtered and distilled to dryness. The residue was dissolved inchloroform and extracted with dilute hydrochloric acid. The acid extractwas made alkaline with ammonia and extracted with chloroform. Thechloroform was distilled off and the residue was dissolved in alcohol.Alcoholic hydrobromic acid was added. On standing, the hydrobromidecrystallized. It was recrystallized from alcohol isopropanol 1:2),yielding l,4-bis(S-dimethylaminopropoxy)anthraquinone hydrobromide ofM.P. ZZZ-224.

5 g. of the hydrobromide obtained above were converted into the freebase with ammonia. The base was extracted with ether and the ether wasdistilled ofi.

The free base obtained as residue above was dissolved in acetone and anexcess of methyl iodide was added. On

Example 12 g. of l,S-dihydroxyanthraquinone and g. of potassiumhydroxide were stirred and heated in 1000 cc. of water. The potassiumsalt dissolved only partially. The hot solution was filtered anddistilled to dryness. The residue was stirred up with 500 cc. of alcoholand filtered by suction. The potassium salt was dried to constant weightover potassium hydroxide in a desiccator.

g. of the potassium salt obtained above were suspended in 300 cc. oftoluene with stirring and 30 g. of 2- diethylaminoethyl chloride wereadded. After cooling, the solution was filtered and distilled todryness. The residue was recrystallized from benzene, yielding'the base1,5 bis(2 diethylaminoethoxy)anthraquinone, of M.P. 126.

5 g. of the base obtained above were neutralized in 50 cc. of alcoholwith alcoholic hydrochloric acid. The hydrochloride was recrystallizedfrom alcohol, yielding the pure compound of M.P. 250. It containedone-half mol of water of crystallization.

6 g. of the base obtained above and 5 cc. of methyl iodide weredissolved in 50 cc. of alcohol. Outstanding. the bis(methiodide) of1,S-bis(Z-diethylaminoethoxy)an? thraquinone crystallized. It wasrecrystallized from methanol and melted at 267.

Example 13 24 'g. of 1,5-dihy'droxyanthraquinone were stirred with 300cc. of xylene. A solution of 12 g. of potassium hydroxide in 40 cc. ofwater was slowly added. The mixture was refluxed until the water hadbeen separated from the condensate. After cooling to about 50,3-diethylaminopropyl chloride (prepared by neutralizing 40 g. of itshydrochloride with an excess of potassium carbonate and extracting with100 cc. of xylene) was added and the mixture was refluxed for 8 hours.The solution was filtered and extracted with dilute hydrochloric acid.The base, 1,S-bis(3-diethylaminopropoxy)anthraquinone, was liberatedfrom the acid extract with ammonia and was extracted with ether. Thedried ether solution was neutralized with alcoholic hydrochloric acid.The hydrochloride separated and was recrystallized from about 400 cc.-ofalcohol, yielding pure 1,5-bis(3-diethylaminopropoxy)anthraquinonehydrochloride, M.P. 221-222.

Example 14 '24 g. of 1,S-dihydroxyanthraquinone were stirred with 350cc. of xylene. A solution of 12 g. of potassium hydroxide in 400 cc. ofwater was slowly added. The mixture was refluxed until the water wasentirely separated from the condensate by a trap. After cooling to about70, the free base (prepared from 37 g. of dimethylaminoisopropylchloride hydrochloride with potassium carbonate and extraction with 100cc. of xylene) was added. The mixture was refluxed for 7 hours, cooledto 30 and filtered. The filtrate was distilled to dryness and theresidue Was dissolved in ether. On addition of alcoholic hydrochloricacid the hydrochloride crystallized slowly. It was purified bycrystallization from a mixture of 300 cc. of isopropanol and 600 cc. ofacetone. The 1,5-bis(2-dimethylaminoisopropoxy)anthraquinonehydrochloride melted at 236-238 and contained onehalf mol of water ofcrystallization.

Example 15 24 g. of 1,S-dihydroxyanthraquinone were suspended in 300 cc.of xylene. A solution of 12 g. of potassium hydroxide in 40 cc. of waterwas slowly added with stirring. The mixture was refluxed until the waterin the condensate was removed by a trap. After cooling to about 30 g. of2-diethylaminoethyl chloride were added and the mixture was refluxed forabout 8 hours. After cooling, it was filtered. From the filtrate thebase was extracted with dilute hydrochloric acid. The free base,1,8-bis(2-diethylaminoethoxy)anthraquinone, was liberated with ammoniaand extracted with ether. The dried ether solution was neutralized withalcoholic hydrochloric acid. The hydrochloride crystallized slowly andwas filtered after one day. Recrystallization from 600 cc. of alcoholand 1200 cc. of acetone yielded pure 1,8-bis(2-diethylaminoethoxy)anthraquinone hydrochloride, M.P. 237-239".

5 g. of the hydrochloride obtained above were dissolved in water andmade alkaline with dilute sodium hydroxide. The free base was extractedwith ether. The ether was distilled oh and the residue wasrecrystallized from isopropanol. The pure base thus obtained melted at73-75".

3 g. of the base obtained above were dissolved in 30 cc. of methanol and15 cc. of a 14% solution of methyl bromide in methanol were added. Afterstanding for 3 days ether was added. The bis(methobromide) of 1,8-bis-(Z-diethylaminoethoxy)anthraquinone separated and was recrystallizedfrom about 200 cc. of isopropanol. It melted at 248-250.

5 g. of the hydrochloride obtained above were converted into free basewith ammonia and extracted with ether. The ether solution was distilledto dryness. The residue was dissolved in acetone and 5 cc. of methyliodide were added. After standing overnight, the methiodide was filteredand recrystallized from cc. meth- 1 9 anol plus 200 cc. ethanol. Thepure compound melted at 234-236. It contained one mol of waterofcrystallization.

Example 16 27 g. of l,8-dihydroxyanthraquinone and 30 g. of potassiumhydroxide were stirred for 2 hours in 400 cc. of water. The solidmonosodium salt of 1,8-dihydroxyanthraquinone was filtered off and driedin a desiccator.

26 g. of the potassium salt of 1,8-dihydroxyanthraquinone were stirredwith 300 cc. of toluene. After addition of 15 g. of 2-diethylaminoethylchloride, the mixture was refluxed for 8 hours. The solution wasfiltered and extracted with 2% hydrochloric acid. On standing, crystalsof the hydrochloride separated. The l-hydroxy- 8 (2diethylaminoethoxy)anthraquinone hydrochloride was recrystallized fromabout 300 cc. of water, M.P. 241-242".

g. of the hydrochloride obtained above were dissolved in water andneutralized with ammonia. The base,1-hydroxy-8-(2-diethylaminoethoxy)anthraquinone, was extracted withether and distilled to dryness.

The free base was dissolved in 60 cc. of alcohol. After addition of 3cc. of methyl iodide, the solution was allowed to stand overnight. Themethiodide was filtered and recrystallized from about 200 cc. ofmethanol, M.P. 228.

Example 17 24 g. of 1,S-dihydroxyanthraquinone were suspended in 300 cc.of xylene. A solution of 12 g. of potassium hydroxide in 40 cc. of waterwas added with stirring. The mixture was refluxed until the water hadbeen removed completely by a trap from the condensate. After cooling to50, a solution of 3-dimethylaminopropyl chloride (prepared byneutralizing 37 g. of its hydrochloride with ammonia and extracting with100 cc. of xylene) was added. 7, The mixture was refluxed with stirringfor 7 hours. After cooling, the solution was filtered and extracted withdilute hydrochloricacid. The acid extract was made alkaline with ammoniaand the base, 1,8-bis- (3-dimethylaminopropoxy)anthraquinone, wasextracted with ether. Addition of alcoholic hydrochloric acidprecipitated the hydrochloride which was filtered after standingovernight. Recrystallization from isopropanol and from alcohol benzenegave pure 1,8-bis(3-dimethylaminopropoxy)anthraquinone hydrochloride,M.P. 213-216. It contains 1 mol of water of crystallization.

Example 18 24 g. of 1,8-dihydroxyanthraquinone were stirred with 300 cc.of xylene. A solution of 12 g. of potassium hydroxide in 50 cc. of waterwas slowly added. The mixture was refluxed until the water was removedfrom the condensate. A solution of Z-dimethylaminoisopropyl chloride(prepared from 37 g. of the hydrochloride with ammonia and extractionwith 100 cc. of xylene) was added and the mixture was refluxed for 7hours. After cooling, the solution was filtered and distilled todryness. The residue was dissolved in ether, filtered and neutralizedwith alcoholic hydrochloric acid. The 1,8-bis(2-dimethylaminoisopropoxy)anthraquinone hydrochloride crystallized slowly.After recrystallization from isopropanol, it melted at 230-231". Itcontains one-half mol of water of crystallization.

4 g. of the hydrochloride obtained above were converted into the freebase, l,8-bis(Z-dimethylaminoisopropoxy)anthraquinone, with ammonia. Thebase was extracted with ether and the ether solution was distilled todryness.

The free base obtained above was dissolved in acetone. After addition of4 cc. of methyl iodide, the mixture was allowed to stand for 3 days. Thecrystals which formed were filtered and recrystallized from 260 cc.isopropanol and 40 cc. water. The bis(methiodide) of 1,8-bis(2-di- I10methylaminoisopropoxy)anthraquinone.contains.l mol of water ofcrystallization, M.P. 251.5-253.

Example 19.

24 g. of 1,4-dihydroxyanthraquinone were stirred with 200 cc. of xylene.A solution of 6 g. of potassium hydroxide in 20 cc. of water was added.The mixture was refluxed and the water was removed from the condensateby means of a trap. When no more water separated, a solution of 14 g. of2-dimethylaminoisopropyl chloride in 100. cc. of xylene was added andthe mixture was refluxed for 10 hours. After cooling, it was filteredand the filtrate was extracted with dilute aqueous hydrochloric acid.From the acid extract .the base was liberated with ammonia and extractedwith benzene. The benzene solution was then distilled to dryness. Theresidue was dissolved in cc. .of acetone and the solu tion was filtered.Alcoholic hydrobromic acid (5%) was added until the solution was acid toCongo red paper. The 1 hydroxy A; (2 --dimethylamino isopropoxy)-anthraquinone hydrobromide crystallized slowly. It was recrystallizedfrom boiling alcohol, M.P. 231-232.

Example 20 48 g. of 1,4'dihydroxyanthraquinone was stirred in a 5 literflask with 1000 cc. of, xylene. A solution of 23 g. of potassiumhydroxide in 60 cc. of water was added slowly at room temperature. Whenthe alkali had been added, the mixture was refluxed with a trap untilall the water was separated. To the suspension of the potassium salt wasthen added a solution of 5 6 g. of 2-dimethy1- aminoisopropyl chloridein 200 cc. of xylene and the mixture was. refluxed for 10-15 hours.After cooling the solids were filtered and the filtrate was distilled todryness. The oily residue was dissolved in dilute aqueous hydrobromicacid and the acid solution was again filtered. Itwas then evaporated todryness. The residue was stirred with 400 cc. of M-butanol for severalhours. The 1,4-bis-(dimethylaminoisopropoxy)anthraquinone dihydrobromidecrystallized and was filtered. It was purified by recrystallization fromalcohol, M.P. 241-242".

I claim:

1. A base selected from the group represented by the formula lower alkyl(I) (Mower alkylene-N ower alkyl I1 3. Acompoundrepresented.bytheuiormula 7 lower anm O-lower alkylene-N n Ilower alkyl lower alkyl (Slower alkylenelower alkyl 4. A compoundrepresented by the formula (I? (Mower alkylene-N H 5. A compoundrepresented by the formula lower alkyl lower alkyl 'N-lower alkylene-O 0O-lower alkylene-N lower alkyl I H lower alkyl 6. A compoundrepresentedby the formula lower alkyl 0 -lower alkylene-N .0 lower alkyl loweralkyl O-1ower alkylene lower alkyl R A B4 wherein R represents a memberof the group consisting of diloweralkyl amino lower alkoxy andmonoheterocyclic lower alkoxy wherein the heterocyclic group is a 5 to 6member nitrogen heterocyclic, one R represents hydrogen and the other Rrepresents hydroxy.

13. 1 hydroxy 2 (2 diethylaminoethoxy)anthraquinone.

14. 1 hydroxy 8 (2 diethylaminoethoxy) anthraquinone.

15. A compound represented by theformula (I? OH lower alkyl -0-loweralkylene-N lower alkyl 16. 1,8 bis (3dimethylaminopropoxy)anthraquinone. 17. 1,8 bis (3dimethylaminopropoxy)anthraquinone hydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS BoydMar. 6, 1956

1. A BASE SELECTED FROM THE GROUP REPRESENTED BY THE FORMULA